Association of maternal plasma manganese with the risk of spontaneous preterm birth: A nested case-control study based on the Beijing Birth Cohort Study (BBCS) in China

Background: As an essential trace nutrient, the effect of plasma manganese (Mn) level on the risk of spontaneous preterm birth (SPB) remains debated. This study aimed to clarify the dynamic changes in plasma Mn concentration during pregnancy and its association with SPB. Methods: A nested case-control study was conducted based on the Beijing Birth Cohort Study (BBCS).This cohort recruited women with a singleton pregnancy, aged 18-44, and intended to receive regular prenatal health care in Beijing Obstetrics and Gynecology Hospital between 2018 and 2020. 244 SPB with maternal plasma samples in the first or third trimester was selected as cases. 244 controls were randomly selected from full term birth mothers with plasma samples in the first or third trimester. Maternal social demographic characteristics and gestational information were obtained from clinical electrical records. Plasma samples were collected in the first and third trimesters for dynamic monitoring. Inductively coupled plasma mass spectrometry (ICP-MS) was used for laboratory analysis.Unconditional logistic regression was used to analyze the relationship between plasma Mn levels and SPB. Results: A total of 488 pregnant women were included for final analysis (SPB N=244; term group N=244). Maternal plasma Mn con centrations increased with gestational age during pregnancy (median, 0.81 ng/ml in the first trimester vs. 1.23 ng/ml in the third trimester). After adjustment for confounders, the highest Mn level (3 rd tertile) in the third trimester increased the SPB risk to 1.647(95%CI: 1.035-2.621).The association became much more significant when the population was stratified to normal weight women(OR: 2.066, 95%CI: 1.182-3.611) or non-premature rupture of membranes（PROM）women (OR: 3.929, 95% CI: 1.995-7.738).Moreover, a dose-dependent relationship exists between the SPB risk and plasma Mn concentration in non-PROMwomen (P trend＜0.001). After excluding women with vaginal group B streptococcus(GBS) infection, the risk association was still significant. Conclusion: High plasma Mn level in the third trimester may be a risk factor for SPB, especially in women with normal weight and non-PROM. It would be helpful for SPB prevention to monitor Mn levels during pregnancy. Trial registration Beijing Birth Cohort Study (BBCS) was retrospectively registered (ChiCTR2200058395, 2022-04-08).